This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the United States, asthma affects 14.6 million people and accounts for economic losses of more than $14 billion a year. Adolescents are the fastest growing asthma demographic, suggesting that the effects of this disease will be felt well into the future. Vasoactive intestinal peptide (VIP) is a critical protein in the initiation and maintenance of allergic airway disease. When acting through its G protein-coupled receptor, VPAC2, it supports a Th2 phenotype, which promotes asthma. It is a neuropeptide with cytokine functionality that is degraded quickly in the na[unreadable]ve lung by neutral endopeptidase produced by the epithelium. When the epithelium is lost during sloughing that occurs in asthma, the peptidase is also lost. As a result of decreased degradation, the actions of VIP are enhanced. We believe that VIP functions to protect the integrity of the damaged pulmonary interface by initiating a fibrotic barrier through the downregulation of matrix metalloproteinase (MMP)-2, which is normally responsible for wound healing and eosinophil efflux into the airway lumen. The proposed experiments are focused to determine the mechanisms by which MMP-2 is regulated and the role of MMP-2 in asthma. The management of this regulation may provide new clinical strategies to treat established airway disease that historically has been difficult to address. A. Specific Aims. Specific Aim 1. Identify the sources of Vasoactive Intestinal Peptide (VIP) in the allergic lung. Hypothesis. VIP is upregulated in asthma and that its production in resident terminal nerve processes and recruited leukocytes changes over the course of the disease model. Specific Aim 2. Determine the extent of VIP's regulation of de novo synthesis of MMP-2. Hypothesis. VIP acts through its VPAC2 receptor to significantly upregulate MMP-2's synthesis. Revised Specific Aim 3. Determine the extent to which the presence of VPAC2 is necessary for the development of inflammation and remodeling in the allergic lung. Hypothesis. VIP acts through VPAC2 receptors to support an allergic remodeling phenotype.